BOARDMEMBERS

Chairman: Prof. Yannick Allanore

Yannick Allanore is Professor of Rheumatology at the Paris Descartes University in Paris since 2008. Professor ALLANORE is the Head of a research group working on the cardiovascular aspects of systemic sclerosis through clinical research programs and basic research ones, including genetic and cellular biology approaches (INSERM U1016, Cochin Institute). He has published over 335 papers in peer-review journals. Professor Allanore is a member of several professional bodies, including the French Rheumatology Society and the American College of Rheumatology. He is the elected chairman (2013-2019) of the The EUROPEAN Scleroderma Trials and Research group (EUSTAR). He is member of the Steering Committee of the Systemic Sclerosis World Congress in charge of Clinical Research committee.

Members of National/International Societies: French Rheumatology Society, American College of Rheumatology, The EULAR Scleroderma Trials and Research group (EUSTAR) (chairman, re-elected in 2016), Association des Sclérodermies de France (head of the scientific committee)

International Advisory Board for the Annual European Workshop of Rheumatology Research (EWRR) since 2011

Program Committee of Member the Annual European League against Rheumatism (EULAR) congress Berlin 2012, London 2013 and Paris 2014

President Annual Meeting of the Swiss Society of Rheumatology (SGR) 2014-2018

Program Committee of the EUSTAR educational course on systemic sclerosis since 2015

Major prizes, awards, fellowships2001 Young Investigator Research Career Award of the University of Zurich2002 European Workshop of Rheumatology Young Investigators Award2002 Academic Exchange Travel Award of ACR and EULAR2003 Abbott Award Basic Science

Our research focus is on systemic sclerosis (SSc), which is a difficult to treat chronic autoimmune disease with high morbidity and mortality. Skin fibrosis is the hallmark of this disease. Our research program spans from a preclinical program focusing on the identification and characterization of key molecules and intracellular signaling cascades that are driving the disease process to a translational and clinical program with emphasis on precision medicine and phase 2/3 clinical trial design. Our Center has been awarded a EULAR Center of Excellence due to the scientific achievements in these areas.

In our preclinical program, we could show that signaling via the Serotonin receptor 2b on fibroblasts is a key mechanism to promote fibrosis in a TGF-b dependent manner in vitro, but also in different animal models of skin fibrosis in vivo (Dees et al, 2011). These promising results led us to perform a proof of concept clinical study in patients with SSc using biomarkers as the primary endpoint. In the investigator-initiated study, we found strong effects on key features of fibrosis confirming the animal studies (Distler et al, paper in preparation). Collaborating with industry, we now designed a phase 3 registration study which has been positively evaluated by the regulatory agencies EMA and FDA and will start later in 2018. We could improve clinical trials design of this study be using biostatistical modeling with large databases, which we co-initiated and organized (Maurer et al 2015, Dobrota et al 2016).

Another focus in the laboratory are epigenetics and non-coding RNAs. In SSc, we have focused on miRNAs as a class of non-coding RNAs. We were the first to show that miR-29 is down regulated in SSc by TGF-β, PDGF-B, and IL-4 and directly contributes to fibrosis by targeting collagen mRNA [Maurer et al, 2010]. This resulted in a patent filed for the use of miR-29 in scleroderma. Furthermore, we have characterized additional miRNAs such as miR-193b and miR-145 as important posttranscriptional regulators in SSc contributing to diverse pathophysiological processes like vasculopathy and fibrosis (Iwamoto et al 2014, Vettori et al, in preparation). Recently, we have identified the novel long non-coding RNA H19X as a key mediator of TGFb profibrotic effects in a variety of mesenchymal cells. Knock-down of H19X completely prevented the profibrotic effects of TGFb. RNA Sequencing and ATAC-Seq showed that these effects are likely mediated by modification of the transcription factor AP-2. H19 X was found to be upregulated in tissues of several fibrotic diseases including SSc (Pachera et al, manuscript in preparation).

Our laboratory has been centrally involved in the identification and characterization of animal models of SSc. For example, there was until recently no animal model available that resembled the vascular changes in human SSc. The further characterization and validation of the Fra-2 tg mice by our groups enabled the use of this animal model as a preclinical model for the vascular (and fibrotic) manifestations of SSc, and it is now one of the most frequently used preclinical model for SSc. We could show that these mice develop skin fibrosis likely mediated by initial apoptosis of endothelial cells, and that the vascular lesions largely resembles finding observed in human SSc tissues (Maurer et al, 2009; Maurer et al, 2012). In addition, we showed that VEGF tg mice develop skin fibrosis in a dose-dependent manner and are more susceptible to inducible models of fibrosis such as the bleomycin model than control wt mice (Maurer et al, 2014).

Translational of our findings into potential clinical applications has always been a focus of our research. We had observed that some of our targets for intervention showed promising results in the animal models, but did not show effects in human proof of concept studies. Using the example of tyrosine kinase inhibitors (Distler, 2007), we could show that the anti-fibrotic effects were strongly depending on the level of activation of the targets, and that in the human disease target activation was often much lower than in the used animal models (Maurer et al, 2013). This lead to change in the use of animal models in preclinical characterization and to updated recommendations how to use animal models in SSc (Jordan et al, 2013). It also highlighted the importance of precision medicine in this disease and led to the development of a molecular imaging program. In this Sinergia funded program, we could recently show that molecular imaging using SPECT or PET/CT in mouse models of SSc allows individual identification of activated pathway involving folate receptor beta (FR-β) and integrin avβ3, paving the way for precision medicine approached against this pathways (Schniering et al, in preparation).

In this report, the strong functional effects of microparticles on the destructive potential of rheumatoid arthritis synovial fibroblasts were described leading to a series of publications in high rank journals in this field.

This comprehensive analysis of serotonin receptor 2 signaling in systemic sclerosis led to an investigator-initiated clinical proof of concept study from my group with positive results. Currently, a large scale phase III randomized placebo-controlled international multicenter registration study is initiated with me as the global PI.

Herein, we could show that hypoxia is an independent driver of fibrosis leading to a vicious circle of fibrosis accumulation and hypoxia. These findings had important impact on the concept of fibrosis as a multifactorial disease that might require multitargeted treatments.

This study defined novel inclusion criteria for randomized controlled clinical trials in systemic sclerosis taking advantage of the large EUSTAR database, which was co-founded by me together with several other colleagues. Several of the ongoing phase three registration trials are using these novel inclusion criteria.

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